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Research report

Crucial role of kainate receptors in mediating striatal kainate

injection-induced decrease in acetylcholine M receptor binding

₁

in rat forebrain

a ,

_*

a b a

Shaoyu Jin

, Jian Yang , Wei Ling Lee , Peter T.H. Wong

a

Department of Pharmacology, Faculty of Medicine, The National University of Singapore, MD2, 18 Medical Drive, Singapore 117597, Singapore b

The National Neuroscience Institute of Singapore, Irrawaddy Block, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore Accepted 15 August 2000

Abstract

We investigated the roles of kainate-,a-amino-3-hydroxy-5-methylisoxazol-4-propionate (AMPA)- and N-methyl-D-aspartate (NMDA)-receptors in mediating striatal kainate injection-induced decrease in the binding of acetylcholine M (NMDA)-receptors in rat forebrain. After₁

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unilateral intrastriatal injection of kainate (4 nmol), the bindings of [ H]kainate (10 nM), [ H]MK-801 (4 nM) and [ H]pirenzepine (4 nM) to the rat ipsilateral forebrain membranes declined, reaching the lowest on day 2 to 4 and recovering on day 8. Saturation binding studies, performed on day 2 post-injection, showed that kainate (1, 2, 4 nmol) dose-dependently decreased Bmax and K of the threed

ligands. (1)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), a selective NMDA receptor channel blocker,

3 3

antagonised (from a dose of 4 nmol) kainate-induced decreases in the bindings of [ H]kainate (up to|20%), [ H]MK-801 (up to|90%)

3

and [ H]pirenzepine (up to |70%). In contrast, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a selective non-NMDA receptor

antagonist, almost completely abolished (from a dose of 12 nmol) kainate-induced decreases in the bindings of all the three ligands (up to

|95–98%). Cyclothiazide, a selective potentiator that enhances AMPA receptor-mediated responses, significantly enhanced (from a dose

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of 4 nmol) kainate-induced decrease in the binding of [ H]kainate but not that of [ H]pirenzepine or [ H]MK-801. In summary, these results indicate that striatal kainate injection-induced decrease in the binding of acetylcholine M receptors in rat forebrain is dependent₁ on activation of kainate receptors and, to a certain extent, a consequent involvement of NMDA receptors. These and previous studies provide some evidence showing that kainate receptors might play a crucial role in regulating excitatory amino acids (EAA)-modulated cholinergic neurotransmission in the central nervous system (CNS).  2000 Elsevier Science B.V. All rights reserved.

Theme: Neurotransmitters, modulators, transporters, and receptors

Topic: Excitatory amino acid receptors: physiology, pharmacology and modulation 3

Keywords: Cholinergic neurotransmission; CNQX; Cyclothiazide; Kainate injection; [ H]Pirenzepine binding

1. Introduction role in mediating excitatory amino acids (EAA)-induced

acetylcholine release in rat striatum in vitro [16], whereas a L-Glutamate, the principal excitatory neurotransmitter in demonstration of kainate receptor-mediated control of the mammalian central nervous system (CNS), mediates cholinergic neurotransmission in the CNS under in vivo most of the excitatory neurotransmission through activa- conditions is still lacking.

tion of three classes of ionotropic glutamate receptors Local injection of a glutamate analogue, such as kainate, [31,34], named after the agonists N-methyl-D-aspartate is widely used as a method for destroying neurones in vivo (NMDA), a-amino-3-hydroxy-5-methylisoxazol-4-prop- [34]. Previous studies have documented that local injection ionate (AMPA) and kainate [39]. Among the three sub- of kainate in rat brain induced massive neuronal loss and types, kainate receptors have been shown to play a distinct over-expression of amyloid precursor protein (APP) [7,12,21] as well as corresponding decreases in the expres-sions of choline acetyltransferase (ChAT) and glutamate

*Corresponding author. Tel.:165-874-6061; fax:165-773-0579.

E-mail address: phcjinsy@nus.edu.sg (S. Jin). decarboxylase [12,14] and in the bindings of ionotropic

glutamate- and acetylcholine muscarinic-receptors [15,25]. hypotonic buffer (1 mM EGTA buffered by Tris–HCl to However, the roles of NMDA-, AMPA- and kainate-re- pH 8.0) and left on ice for 30 min. The lysed membranes ceptors in these mechanisms are poorly understood. Gener- were collected by a 30-min centrifugation at 40 0003g,

ally, the effect of kainate is thought to be indirect through and then the lysis / centrifugation step was repeated one innervations of glutamatergic neurons [10]. It is the release more time. The membranes were then suspended and of glutamate [11,26] that leads to neuronal death through washed twice in a Tris–acetate buffer (100 mM, pH 7.4). activation of postsynaptic NMDA receptors [27,34]. These After each centrifugation, the membrane suspension was studies focusing on rat hippocampus suggested an excitat- sonicated with a tip sonicator at high intensity. The final ory role for presynaptic kainate receptors on glutamatergic pellet was suspended in the assay buffer (100 mM HEPES terminals [27]. On the other hand, conflicting observations containing 50 mM EGTA buffered to pH 7.4 by Tris– regarding the roles of presynaptic kainate- and postsynap- HCl). The membrane suspension was stored in aliquots at tic NMDA-receptors have also been reported [5,6,12]. 2808C.

We have recently observed that striatal kainate injection

induced a loss in cholinergic neuron and an increase in 2.3. Protein analysis APP expression in rat forebrain. These effects are

depen-dent on the activation of kainate receptors with a con- On the day of the binding assay, the frozen membrane sequent involvement of NMDA receptors [42]. In the preparations were thawed on ice and their protein contents present studies, we, therefore, investigated the roles of were determined by Bradford’s method [4]. Bovine serum kainate-, AMPA- and NMDA-receptors in mediating striat- albumin was used for the standard curve. The membrane al kainate injection-induced decreases in the bindings of preparations (protein 0.4 mg / ml) were kept on ice until

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ionotropic glutamate- and acetylcholine M -receptors by1 used in [ H]kainate, [ H]MK-801 and [ H]pirenzepine 3

examining the characteristics of the specific [ H]kainate, binding assays.

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[ H]MK-801 and [ H]pirenzepine binding to the

mem-branes prepared from the rat ipsilateral forebrain. 2.4. Radioligand binding assays

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[ H]Kainate, [ H]MK-801 and [ H]pirenzepine bindings

2. Materials and methods were studied, using the filtration method [8,23,38]. All the

binding incubations were performed in disposable sterile

2.1. Animal treatment 96-well plates in a total volume of 300ml and terminated

by rapidly filtering the incubation medium through What-Male Sprague–Dawley rats (200–250 g) were housed man GF / B glass fiber filters under suction by means of a under controlled conditions with a 12-h day-night cycle Skatron cell harvester.

3

and with food and water available ad libitum. Rats were For [ H]kainate binding, aliquots of the membrane anesthetized with chloral hydrate (400 mg / kg, i.p.) and suspension (in a final concentration of 200 mg / ml) were

3

mounted in a stereotaxic apparatus (Stoelting, Wood Dale, incubated with [ H]kainate (10 nM) on ice for 1 h. IL, USA). One ml of phosphate buffer (4 mM, pH 7.4) Non-specific binding, determined by inclusion of 1 mM with kainate was slowly injected unilaterally into the L-glutamate, amounted to 10–12% of the total binding. For striatum (AP510.7 mm, ML563.0 mm, DV526.5 mm the saturation experiments, the membranes were incubated

3

from bregma), with 5 min allowed for local diffusion with 0.8–400 nM [ H]kainate. Non-specific binding before removing the microsyringe. The antagonists (1)-5- amounted to 10–40% of the total binding. The Skatron cell Methyl-10,11-dihydro-5H-dibenzo[a, d]cyclohepten-5,10- harvester was set at 111 which meant the filters were imine (MK-801) or 6-cyano-7-nitroquinoxaline-2,3-dione washed with three 1-ml aliquots of ice-cold 50 mM Tris– (CNQX) was injected 15 min before the kainate injection. HCl buffer, pH 7.4 (total filtering and washing time was

Cyclothiazide was coinjected with kainate. 3 s).

3

For [ H]MK-801 binding, aliquots of the membrane

2.2. Membrane preparation suspension (in a final concentration of 200mg / ml with 10

mM glutamate and 10 mM glycine) were incubated with 3

Rats were decapitated without prior stunning or anaes- [ H]MK-801 (4 nM) at 258C for 2.5 h. Non-specific thesia, and the forebrains were rapidly removed on ice. binding, determined by inclusion of 100 mM MK-801, Membrane preparations were prepared as previously de- amounted to 5–8% of the total binding. For the saturation scribed [22]. In brief, the ipsilateral forebrains were experiments, the membranes were incubated with 0.5–150

3

3

For [ H]pirenzepine binding, aliquots of the membrane from Research Biochemicals (RBI, Natick, MA, USA). All suspension (in a final concentration of 200mg / ml with 1 other chemicals were of analytical purity and of commer-mM KCl and 1 commer-mM MgCl ) were incubated with2 cial origin.

3

[ H]pirenzepine (4 nM) at 258C for 3 h. Non-specific binding, determined by inclusion of 1 mM atropine,

amounted to 6–8% of the total binding. For the saturation _{3. Results} experiments, the membranes were incubated with 0.5–100

3

3 3

nM [ H]pirenzepine. Non-specific binding amounted to _{3.1. Time-courses of [ H]kainate, [ H]MK-801 and} 3

6–45% of the total binding. The Skatron cell harvester was _{[ H]pirenzepine binding} set at 333 which meant the filters were washed with three

3-ml aliquots of ice-cold 50 mM Tris–HCl buffer, pH 7.4 _{After unilateral intrastriatal injection of kainate (4} 3

(total filtering and washing time was 9 s). _{nmol), the specific bindings of [ H]kainate (10 nM),}

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[ H]MK-801 (4 nM) and [ H]pirenzepine (4 nM) to the

2.5. Scintillation counting membranes prepared from the ipsilateral striatum (results

not shown), cortex (results not shown) and forebrain (Fig. The filters were transferred to scintillation vials and 1) of rat clearly declined. Among them, the specific

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soaked in 3 ml of BCS (Amersham, Arlington Heights, IL, bindings of [ H]kainate and [ H]MK-801 declined to the USA) scintillation cocktail. The vials were shaken and left lowest (about 33 and 19%, respectively) on day 2 and overnight at room temperature, and shaken again before recovered on day 8 post-injection (Fig. 1A and 1B),

3

being counted in a Beckman LS 3801 liquid scintillation whereas the specific binding of [ H]pirenzepine declined counter with an efficiency of 56% for tritium. to the lowest (about 38%) on day 4 and did not recover

until day 8 post-injection (Fig. 1C). 2.6. Calculation and statistical analysis

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3.2. Saturation-curves of [ H]kainate, [ H]MK-801 and 3

Specific binding was calculated as the difference be- [ H]pirenzepine binding tween total and non-specific binding and expressed on a

protein basis (pmol / mg protein). Receptor density (Bmax) Saturation binding experiments were performed on day and dissociation constant (K ) values were determinedd 2 after unilateral intrastriatal injections of kainate (1, 2, 4 from saturation binding data by a computerized non-linear nmol). Kainate, in a dose-dependent manner, declined

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regression analysis (GRAPHPAT PRISM 2.0, GraphPat Soft- saturation-curves of the specific [ H]kainate, [ H]MK-801

3

ware, San Diego, CA, USA). and [ H]pirenzepine binding to the rat ipsilateral forebrain

Scatchard analysis of the data was not used for the membranes (Fig. 2(1)). Their Kd and Bmax values are determination of binding parameters (Kd and Bmax), but shown in Table 1.

plotted primarily to visualize the different binding models, The Scatchard plot of the saturation binding of 3

curvilinearity for multiple binding sites and linearity for a [ H]kainate was curvilinear, indicating more than one single binding site. The best-fit model was determined population of receptor binding sites [Fig. 2(2A)]. F-test

using the F-test. indicated that a two-site fit of the data was significantly

Total binding and non-specific binding for each sample better than a one-site fit (P,0.05). In contrast, the 3 were determined in triplicate. All data were the results of Scatchard plot of the saturation binding data of [

H]MK-3

at least three independent experiments using at least three 801 [Fig. 2(2B)] or [ H]pirenzepine [Fig. 2(2C)] was rats per experiment and given as means6S.E.M. One-way linear, indicating only one apparent population of receptor analysis of variance (ANOVA) was employed followed by binding site. F-test indicated that a two-site fit of the data Bonferroni post-hoc analysis for multiple comparisons. A was not significantly better than a one-site fit (P.0.05). probability level of,0.05 was considered significant.

3.3. Differential antagonism by MK-801 and CNQX of

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2.7. Chemicals kainate-induced decreases in[ H]kainate, [ H]MK-801

3

and[ H]pirenzepine binding 3

[ H-Vinylidene]kainate (specific activity: 58 Ci / mmol), 3

[ H](1)MK-801 (specific activity: 22.5 Ci / mmol), and MK-801 and CNQX dose-dependently antagonised kain-3

ate (4 nmol)-induced decreases in the specific bindings of [ H]pirenzepine (specific activity: 85.6 Ci / mmol) were

3 3

[ H]kainate (10 nM), [ H]MK-801 (4 nM) and purchased from NEN Life Science Products (Boston, MA,

3

USA). Glycine, kainic acid, L-glutamic acid and HEPES [ H]pirenzepine (4 nM) to the rat ipsilateral forebrain (N-[2-hydroxyethyl] piperazine-N9-[2-ethanesulfonic acid]) membranes (Fig. 3). The antagonism by MK-801, from a were purchased from Sigma Chemical (St. Louis, MO, dose of 4 nmol, reached a maximum of only about 20% for

3

3 3 3

3 3 3

3

specific [ H]MK-801 binding and about 70% for the 3

specific [ H]pirenzepine binding. On the other hand, CNQX at a dose of 12 nmol almost completely abolished kainate (4 nmol)-induced decreases in the specific bindings of all the three ligands (about 95–98%).

3.4. Selective potentiation by cyclothiazide of

kainate-3 3

induced decreases in[ H]kainate, [ H]MK-801 and 3

[ H]pirenzepine binding

Cyclothiazide, in a dose-dependent manner, significantly enhanced kainate (4 nmol)-induced decrease in the specific

3 3

binding of [ H]kainate (10 nM) but not that of [ H]MK-3

801 (4 nM) or [ H]pirenzepine (4 nM) to the rat ipsilateral forebrain membranes (Fig. 4). The potentiation by cyclothiazide, from a dose of 4 nmol, reached a maximum

3

of about 15% for the specific [ H]kainate binding.

4. Discussion

4.1. Kainate-induced decrease in acetylcholine M1 receptor binding

The present studies demonstrated that kainate injected unilaterally into the striatum dose-dependently decreased the bindings of ionotropic glutamate- and acetylcholine M -receptors in the ipsilateral forebrain of rat, particularly1 on day 2 to 4 post-injection. These results are in agreement with previous observations, using immunohistochemistry, histochemistry, histofluorescence, and electron microscopic techniques [7,42], that on day 2 after intrastriatal injection of kainate, there were a massive neuronal loss and a significant reduction of ChAT expression in the ipsilateral forebrain of rat. Considered together, these findings sug-gest that the decrease in the binding of acetylcholine M1 receptors in the present experimental model, at least to a certain extent, reflects a loss of cholinergic neurons [28,40].

4.2. Roles of NMDA-, AMPA- and kainate-receptors

Saturation binding experiments of radiolabeled kainate, MK-801 and pirenzepine were performed to mainly assess kainate-, NMDA- and acetylcholine M -receptor binding1 sites. The selective NMDA receptor channel blocker, MK-801, and the selective non-NMDA receptor antagonist, CNQX, were used to distinguish between NMDA- and non NMDA-receptor-mediated responses. The present results showed that CNQX and MK-801 differentially antagonised

3

Fig. 2. (2) Scatchard plots of the saturation bindings of [ H] kainate the kainate-induced decrease in acetylcholine M receptor1

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(0.8–400 nM, A), [ H]MK-801 (0.5–150 nM, B) and [ H]pirenzepine _{binding. We have further extended this observation to} (0.5–100 nM, C) to the rat ipsilateral forebrain membranes. Data come

include the kainate-induced neuronal loss and decrease in

from controls in Fig. 2(1). The Scatchard analysis of data was not used

ChAT expression [42]. Cyclothiazide is a selective

poten-for any determinations of binding parameters (K and Bd max), but plotted

tiator that enhances AMPA receptor-mediated responses

Table 1

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K (nM) and Bd max(pmol / mg protein) of the bindings of [ H]kainate (0.8–400 nM), [ H]MK-801 (0.5–150 nM) and [ H]pirenzepine (0.5–100 nM) to the a

rat ipsilateral forebrain membranes

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Injection [ H]Kainate binding [ H]MK-801 binding [ H]Pirenzepine binding

Kd Bmax Kd Bmax Kd Bmax

Saturation assays were performed on day 2 after kainate (1, 2, 4 nmol) was unilaterally injected into rat striatum. Data are expressed as the mean6S.E.M of nine to 12 observations from at least three independent experiments, using at least three rats per experiment.

b

A significant difference P,0.05 (by one-way ANOVA with Bonferroni) vs. corresponding uninjected control. c

A significant difference P,0.01 (by one-way ANOVA with Bonferroni) vs. corresponding uninjected control. d

A significant difference P,0.001 (by one-way ANOVA with Bonferroni) vs. corresponding uninjected control.

[2,16]. In the present studies, cyclothiazide was used to bral cortex and hippocampus have established the localiza-differentiate the involvement of the AMPA- and kainate- tion of AMPA receptors at postsynaptic densities [33] as receptors since CNQX was able to almost completely well as at the developed dendrites [9,31]. However, an block the kainate-induced decreases in all three bindings. observation using autoradiography indicated the localiza-The decrease in the binding of radiolabeled kainate in- tion of AMPA receptors on presynaptic endings of dopa-duced by cyclothiazide shows the potentiation of AMPA mine fibres [41], which is supported by our previous receptor-mediated responses, which is in agreement with studies regarding dopamine release from the presynaptic previous findings [22]. However, cyclothiazide did not endings of dopamine fibres [16,17] and by a previous enhance kainate-induced decrease in the binding of acetyl- finding that dopamine positively mediated only GluR1

choline M receptors.1 gene expression [1]. To date, there is no evidence showing

These results indicate that the activation of NMDA the presence of excitatory presynaptic AMPA receptors on receptors accounts for a substantial fraction of kainate- cholinergic and glutamatergic neurons.

induced decrease in the binding of acetylcholine M1 More importantly, these results demonstrate a key role receptors in rat forebrain, which support most of the of kainate receptors in mediating kainate-induced decrease previous studies regarding the involvement of NMDA in the binding of acetylcholine M receptors in rat fore-1 receptors in kainate-induced brain injury [11,26,27,42]. brain, consistent with our other findings regarding the Radioligand binding and immunohistochemical studies distinct role of kainate receptors in mediating kainate-have shown that NMDA receptors are distributed through- induced acetylcholine release in rat striatum [16] and out the rat brain but predominantly within the forebrain, cholinergic neuron loss in rat forebrain [42]. Immuno-and mainly localized at postsynaptic densities Immuno-and the cytochemical studies, using antibodies against kainate associated dendrites of most neurons [31], including receptor subunits, have clearly shown the presence of cholinergic neurons [17]. The activation of postsynaptic kainate receptors at both the presynaptic and postsynaptic NMDA receptors on target cells may trigger cytotoxic densities in the rat brain [32,35]. In the present experimen-actions by opening calcium channels [3] and evoke exces- tal model, the involvement of kainate and NMDA re-sive release of neurotransmitters including acetylcholine by ceptors suggest that both the pre- and post-synaptic kainate depolarising cell membranes [17,18]. Both the cytotoxic receptors might participate in mediating the effects of actions and acetylcholine release induced by excessive kainate. The mechanism underlying the link between the activation of postsynaptic NMDA receptors might directly activation of kainate receptors and the involvement of contribute to the effects of NMDA receptors in the present NMDA receptors is a controversial issue. It might be

experimental model. attributed to a presynaptic excitation on glutamatergic

Fig. 3. Effects of increasing doses of MK-801 (filled symbols) or CNQX (unfilled symbols) on kainate (4 nmol)-induced decreases in the bindings of

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3 3

Fig. 4. Effects of increasing doses of cyclothiazide on kainate (4 nmol)-induced decreases in the bindings of [ H]kainate (10 nM), [ H]MK-801 (4 nM) 3

and [ H]pirenzepine (4 nM) to the rat ipsilateral forebrain membranes. Binding assays were performed on day 2 after kainate (4 nmol) with or without cyclothiazide was unilaterally injected into rat striatum. Each bar is the mean6S.E.M of nine to 16 observations from at least three independent experiments, using at least three rats per experiment. A significant difference (by one-way ANOVA with Bonferroni) vs. corresponding control (kainate 4 nmol) is represented by: * P,0.05, ** P,0.01, *** P,0.001.

4.3. Kainate receptors and the cholinergic kainate receptors could not be ruled out because of the lack

neurotransmission in the CNS of high selectivity of NBQX and CNQX on AMPA- and

kainate-receptors.

The present receptor binding results are consistent with Loss of cholinergic neurons in the basal forebrain is those obtained in neurotransmitter release [16] and im- believed to account for much of the learning and memory munohistochemistry [42] studies. These results indicate deficits in Alzheimer’s disease. It was reported that that kainate receptors are predominantly involved in the domoate, a glutamate analogue produced by mussels, EAA-induced increase in acetylcholine release, decrease in caused a syndrome with features that resemble those of M receptor binding and ChAT immunoreactivity, increase1 Alzheimer’s disease in a group of Newfoundlanders after in APP immunoreactivity, and neuronal loss. They might consuming domoate-contaminated mussels in 1987 suggest a crucial role for kainate receptors in regulating [29,36,37]. Domoate has been established to be a relatively EAA-modulated cholinergic neurotransmission in the CNS selective agonist at kainate receptors although it can still as well as a similar role for the receptors in the CNS act on AMPA receptors [20]. The present studies may help diseases associated with cholinergic disorders e.g. Al- to understand the mechanism of neurodegeneration under-zheimer’s disease on the basis of the cholinergic hypoth- lying the domoate-induced syndrome.

esis of this neurodegenerative disease [13,24].

The main functions ascribed to cholinergic pathways are

related to arousal and learning, and motor control. Block- 5. Conclusion ade of glutamatergic transmission by CNQX and NBQX

[13] P.T. Francis, A.M. Palmer, M. Snape, G.K. Wilcock, The cholinergic

dependent on the activation of kainate receptors and, to a

hypothesis of Alzheimer’s disease: a review of progress, J. Neurol.

certain extent, a consequent involvement of NMDA

re-Neurosur. Psychiat. 66 (1999) 137–147.

ceptors. These results support the possibility that both the _{[14] B.H. Guevara, I.S. Hoffmann, L.X. Cubeddu, Ventral and dorsal} pre- and post-synaptic kainate receptors participate in striatal cholinergic neurons have different sensitivities to kainic acid,

mediating the effects of kainate in the present experimental Neurochem. Int. 31 (1997) 723–730.

[15] R.E. Hruska, R. Schwarcz, J.T. Coyle, H.I. Yamamura, Alterations

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acid injections, Brain Res. 152 (1978) 620–625.

EAA-modulated cholinergic neurotransmission in the _{[16] S. Jin, AMPA- and kainate-receptors differentially mediate}

excitat-CNS. ory amino acid-induced dopamine and acetylcholine release from rat

striatal slices, Neuropharmacology 36 (1997) 1503–1510. [17] S. Jin, B.B. Fredholm, Role of NMDA, AMPA and kainate receptors

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[18] S. Jin, B.B. Fredholm, Glucose deprivation increases basal and

This work was supported by grants (3981319 / 3981320)

electrically evoked transmitter release from rat striatal slices. Role of

to PTHW from The National University of Singapore.

NMDA- and adenosine A receptors, Eur. J. Pharmacol. 340 (1997)1 169–175.

[19] S. Jin, B. Johansson, B.B. Fredholm, Effects of adenosine A and1 A receptor activation on electrically evoked dopamine and acetyl-2

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